title: Discovery of a linear peptide for improving tumor targeting of gene products and treatment of distal tumors by IL-12 gene therapy.
abstract: Like many effective therapeutics, interleukin-12 (IL-12) therapy often causes side effects. Tumor targeted delivery may improve the efficacy and decrease the toxicity of systemic IL-12 treatments. In this study, a novel targeting approach was investigated. A secreted alkaline phosphatase (SEAP) reporter gene-based screening process was used to identify a mini-peptide which can be produced in vivo to target gene products to tumors. The coding region for the best peptide was inserted into an IL-12 gene to determine the antitumor efficacy. Affinity chromatography, mass spectrometry analysis, and binding studies were used to identify a receptor for this peptide. We discovered that the linear peptide VNTANST increased the tumor accumulation of the reporter gene products in five independent tumor models including one human xenogeneic model. The product from VNTANST-IL-12 fusion gene therapy increased accumulation of IL-12 in the tumor environment, and in three tumor models, VNTANST-IL-12 gene therapy inhibited distal tumor growth. In a spontaneous lung metastasis model, inhibition of metastatic tumor growth was improved compared to wild-type IL-12 gene therapy, and in a squamous cell carcinoma model, toxic liver lesions were reduced. The receptor for VNTANST was identified as vimentin. These results show the promise of using VNTANST to improve IL-12 treatments.
authors.affiliation: Department of Pediatrics, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jeffry
authors.initials: J
authors.lastname: Cutrera
authors.forename: Denada
authors.initials: D
authors.lastname: Dibra
authors.forename: Xueqing
authors.initials: X
authors.lastname: Xia
authors.forename: Azeem
authors.initials: A
authors.lastname: Hasan
authors.forename: Scott
authors.initials: S
authors.lastname: Reed
authors.forename: Shulin
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics*; D002352:Carrier Proteins; D002846:Chromatography, Affinity; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D018664:Interleukin-12 / Q000235:genetics* / Q000494:pharmacology / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D014746:Vimentin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D011993:Recombinant Fusion Proteins; D014746:Vimentin; D018664:Interleukin-12